TheEffectsofContinuousBloodPuriﬁcationfor SIRS...

International Scholarly Research NetworkISRN HematologyVolume 2012, Article ID 986795, 10 pagesdoi:10.5402/2012/986795

Clinical Study

The Effects of Continuous Blood Purification forSIRS/MODS Patients: A Systematic Review and Meta-Analysis ofRandomized Controlled Trials

Tian Hongliang,1, 2 Zeng Rong,1, 3 Wang Xiaojing,4 Sun Rao,1, 2 Li Lun,1, 2 Tian Jinhui,1

Cao Nong,3 and Yang Kehu1

1 Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China2 The Second Hospital of Lanzhou University, Lanzhou 730000, China3 The First Hospital of Lanzhou University, Lanzhou 730000, China4 Peking Union Medical College Hospital, Beijing 100730, China

Correspondence should be addressed to Cao Nong, [email protected] and Yang Kehu, [email protected]

Received 4 April 2012; Accepted 2 May 2012

Academic Editors: D. Del Principe and I. C. Haznedaroglu

Copyright © 2012 Tian Hongliang et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Background. Continuous veno-venous hemofiltration (CVVH) has aroused great concern in recent years because its effect onclearing inflammatory mediators and its mechanism of clinical effects in the treatment of critical illness has also become a researchdirection. Objective. To evaluate the efficacy of continuous blood purification for systemic inflammatory response syndrome(SIRS)/multiple organ dysfunction syndrome (MODS) patients. Methods. A systematic review of the literature was undertakento assess randomized controlled trials on CVVH. Results. 11 RCTs involving a total of 414 patients were included. Comparedwith the control group, CVVH for SIRS/MODS patients has several advantages including better effects on clearing the plasmainflammatory mediators IL-6 [SMD3d = −0.45, 95%CI, (−0.83, −0.07), SMD7d = −1.07, 95%CI, (−1.52, −0.62)], on plasmaTNF-alfa [SMD3d = −0.87, 95%CI, (−1.69, −0.04), SMD7d = −1.42, 95%CI, (−2.49, −0.35)], lower white blood cell (WBC)count [MD = 2.61, 95%CI, (1.49, 3.73)], shorter hospital stays [MD = −7.21 days, 95%CI, (−10.68, −3.74)] and better stabilityof hemodynamics. However, there is no significant difference in the mortality rate [MODS:RR = 0.62, 95%CI, (0.38, 1.01),SIRS:RR = 0.75, 95%CI, (0.57, 1.08)]. Conclusions. The study showed that CVVH was able to eliminate inflammatory mediators(TNF-alfa, IL-6) in plasma effectively, lower WBC count and shorter hospital stays than conventional therapeutic measures.

1. Introduction

Continuous blood purification (CBP) has now been exten-sively employed for the management of systemic inflamma-tory response syndrome (SIRS), and even multiple-organdysfunction syndrome (MODS) in critically ill patients [1].To those patients, some treatments had been put forwardtargeting on them like monoclonal antibodies (such as anti-TNF antibody), receptor antagonists (such as anti-PAF),and soluble receptors (e.g., TNFR), yet none of these canprevent the release of inflammatory mediators satisfactorilynor remove existing inflammatory mediators, especiallyTNF-alfa, as a larger molecular weight trimer (54 kd) hasbecome a difficulty of internal clearance. Hemofiltration iscommonly used in an intensive care unit setting which is

also called continuous venovenous hemofiltration (CVVH)or continuous renal replacement therapy (CRRT). One of theimportant mechanisms of hemofiltration is that it may playa role in removed inflammatory mediators [2]. Amongst themediators, the proinflammatory cytokines tumor necrosisfactor (TNF-alfa) and interleukin-6 (IL-6) are thought tooccupy a key position in the chain of events leading to shock.

Some trials support this view, but at the same time,some trials say there is no significant evidence found inthe relationship between hemofiltration and inflammatorymediators [3, 4]. So there is still controversy regarding thisproblem.

The objective of this study is to evaluate the outcomesof CVVH versus control group for SIRS/MODS patients.Moreover, we investigated whether the use of CVVH would

2 ISRN Hematology

result in an improvement of mortality, total duration of hos-pital stays, white blood cell (WBC) count, and hemodynamicstability in patients, respectively.

2. Methods

The Preferred Reporting Items for Systematic reviews andMeta-Analyses (PRISMA) was used to conduct data extrac-tion.

2.1. Study Selection. We searched electronic databases fromPubMed (1966–2011.10), the Cochrane Library (Issue 4,2011), EMBASE (1974–2011.10), Science Citation Index(1974–2011.10), the China Journal Fulltext Database (1994–2011.10), Chinese Scientific Journals Fulltext Database(1989–2011.10), Chinese Biomedical Literature Database(1978–2011.10), with the terms (continuous’ venove-nous hemofiltration), (continuous renal replacement ther-apy), (continuous arteriovenous hemofitration), (continu-ous blood purification), in combination with the medicalsubject headings. Relevant articles referenced in these pub-lications were downloaded from the databases. The relatedarticle function also was used to widen the search results. Allabstracts, comparative studies, nonrandomized trials, andcitations scanned were searched comprehensively. We alsohand-searched the reference lists of every primary studyfor additional publications. Further searches were done byreviewing abstract booklets and review articles. Trials wereincluded irrespective of the language in which they werereported.

2.2. Data Extraction. Each study was reviewed by 2 re-searchers for reliability of our meta-analysis. Only random-ized controlled trials on CVVH versus conventional thera-peutic measures for inflammatory mediators removal wereincluded in the meta-analysis. Two researchers extracteddata separately and if there was any controversial, it wasconfirmed by the third researcher.

2.3. Inclusion Criterion. The inclusion criteria for this analy-sis were randomized controlled trials that compared CVVHwith conventional therapeutic measures about patientswith critically inflammatory states (systemic inflammatoryresponse syndrome or multiple-organ dysfunction syn-drome) [5].

2.4. Exclusion Criteria. Trials were excluded if included pa-tients were pregnant, younger than 18 years, in a moribundstate, in chronic renal failure, or receiving immunosuppres-sive therapy.

2.5. Statistical Analysis. We summarized available data fromall trials reporting results. Computing pooled risk ratios (RR)and their respective 95% confidence intervals by means of afixed-effects meta-analysis model. For continuous data, themean difference (MD) is recommended when all trials usethe same scale to report their outcomes, while standardizedmean difference (SMD) is more appropriate when trials use

different scales to report their outcomes, just as data abouteffects on clearing the plasma inflammatory mediators in thefollowing. All statistical analysis was performed with ReviewManager (version 5.1). We used the chi2 statistic to assessheterogeneity between trials and the I2 statistic to assessthe extent of inconsistency. Subgroup analysis was intendedto explore important clinical differences among trials thatmight be expected to alter the magnitude of treatment effect.

3. Results

From Figure 1 can be seen the flow chart of studies frominitial results of publication searches to final inclusion [6–16]. 11 trials about CVVH versus conventional therapeuticevaluate the efficacy of inflammatory mediator removalsencompassing a total of 438 patients which were retrievedfrom the electronic databases. Standard deviations were notreported in the majority of studies, where necessarily wereestimated either by means of ranges or P values. Character-istics of each trial were given in Table 1. Included studies’methodological quality was assessed using the Cochranehandbook in Table 2 [17].

3.1. Mortality. Statistical heterogeneity was basically wellamong studies (P = 0.25, I2 = 22%) [6–14, 16]. There wasno significant difference in mortality between CVVH andControl group (MODS : RR = 0.62, 95%CI, (0.38, 1.01),SIRS : RR = 0.75, 95%CI, (0.57, 1.08)) (Table 3).

3.2. Hospital Stay. Two studies reported the data of lengthof hospital stay [11, 14]. CVVH group was associated withsignificantly shorter hospital stays (MD = −7.21 days,95%CI, (−10.68, −3.74)). Study Cole et al. [9] reportedCVVH group shorten the length of stay in the ICU from aKaplan-Meier analysis (Table 4).

3.3. CVVH versus Control on Plasma IL-6 Change. Threestudies [10, 11, 15] reported at three-day and seven dayfollowup, CVVH group had better effects than Control groupon plasma IL-6 change [SMD3d = −0.45, 95%CI, (−0.83,−0.07), SMD7d = −1.07, 95%CI, (−1.52, −0.62)] (Table 5).

3.4. CVVH versus Control Group on Plasma TNF-Alfa Change.There was three trials [10, 11, 15] reported, CVVH versuscontrol on plasma TNF-alfa, significant heterogeneity existedamong trials (P = 0.07, I2 = 69%), (P = 0.01, I2 = 84%).CVVH group have better effects than Control group onplasma TNF-alfa change (SMD3d = −0.87, 95%CI, (−1.69,−0.04)), (SMD3d = −1.42, 95%CI, (−2.49, −0.35))(Table 6).

3.5. WBC Count Reduction. WBC count reported in two tri-als was significantly reduced in CVVH group (MD = 2.61,95%CI, (1.49, 3.73)) [13, 15] (Table 7).

3.6. Hemodynamic Variables. Two trials reported hemody-namic descriptive analysis stability [6, 7]. Riera et al. 1997

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Trials identified as potentially relevant and screened for retrieval

- Cochrane Library (n = 47) - PubMed (n = 449)

- EMBASE (n = 805) - SCI (n = 351)

- WanFang Database (n = 111)

Excluded on the basis of title and abstract (n = 1896)

Potentially appropriate trials for more detailed assessment (n = 98)

Studies excluded with reasons (n = 87)

- Double records (n = 2)

- Incomplete information on outcomes (n = 44)

- Observational study (n = 34)

- Review articles (n = 7)

11 trials were included in this meta-analysis

n = 173)- The China Journal Fulltext Database (

n = 201)- Chinese Scientific Journals Fulltext Database (

Figure 1: Flow diagram of trial selection.

Table 1: Baseline characteristics of the included studies.

TrialsSamplesize (n)

Country Disease Illness severity scores AgeFilter

membraneBlood flow(mL/min)

Treatment

Sander 1997 [6] 13/13 Germany SIRS 15.3± 1.4/13.9± 1.2A 58±3.0/52±3.2 AN69 150 mL/minCVVH∗ versus

control

Sanchez Riera1997 [7, 8]

15/15 Spain MODS 22± 7/21± 6A 36± 18/36± 14 AN69 130 mL/minCVVH∗ versus

control

Cole et al.2002 [9]

12/12 Australia MODS 21.8± 4/22.2± 6.4AMedian (IQR)

65.5 (22.0)/68.0 (19.0)

AN69 200 mL/minCVVH∗ versus

control

Liu et al.2003 [10]

24/26 China MODS 25± 7/23± 7A 39± 11/37± 19 AN69 +PS200–

250 mL/minCVVH∗ versus

control

Yang et al.2004 [11]

22/15 China SIRS 14.8± 4.5/14.6± 4.7A 44.6±15.4/44.6± 15.4

PS150–


control

Ding and Zhao2007 [12]

11/10 China MODS 14.1± 3.6/14.1± 3.6A 23–78/23–78 PS Not reportedCVVH∗ versus

control

Yang and Hoyang2008 [13]

31/27 China SIRS 18.6± 3.4/17.9± 2.7A 31.5±10.9/31.5± 10.9

PS180–


control

Peng et al.2008 [14]

17/15 China SIRS18.21± 2.58/17.65±

3.14A 28–70/30–69 AN69250–


control

Zhang et al.2006 [15]

30/30 China SIRS Not reported46.7±

18.3/46.7± 18.3PS

150–200 mL/min

CVVH∗ versuscontrol

Payen et al.2009 [16]

37/39 France SIRS 11.6± 3.4/10.4± 2.9B 57.6±12.6/58.6± 13.5

PS 150 mL/minCVVH∗ versus

control

MODS: multiple-organ dysfunction syndrome.SIRS: systemic inflammatory response syndrome.CVVH∗ group: CVVH + conventional therapeutic measures.Control group: conventional therapeutic measures.A: acute physiology and chronic health evaluation, APACHE II score; B: simplified acute physiology score, SOFA score.

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Table 2: Methodological quality of included studies.

Trials Randomization Allocation concealment Blinding Incompleteoutcome data ITT analysis

Sander Yes Not stated Non blind Yes Not stated

Sanchez Riera Yes, random schedule Yes Not stated Yes Not stated

Cole Yes, random number table Opaque-sealed envelopment Not stated Yes Yes

Liu Yes Not stated Not stated Yes Not stated

Yang Yes Not stated Not stated Yes Not stated

Ding Yes Not stated Not stated Yes Not stated

Yang Yes Not stated Not stated Yes Not stated

Peng Yes Not stated Not stated Yes Not stated

Zhang Yes, random number table Not stated Not stated Yes Not stated

Payen Yes, by blocks of four Not stated Not stated Yes Yes

[7] reported that there is a significant improvement in meanarterial pressure (80 ± 9 to 94 ± 8 mmHg, P = 0.01)and partial pressure of oxygen in arteria blood/inspiratoryoxygen supply index (124 ± 40 to 204 ± 44, P = 0.03)in the intervention group during the study period. Sanderet al. 1997 [6] reported the mean arterial pressure andsystemic vascular resistance index tended to increase in thehemofiltration group, but not in the control group.

4. Discussion

The important effect of inflammatory mediators in thedevelopment of SIRS and MODS is recognized. As one ofthe earliest released inflammatory mediators, TNF-alfa canactivate a large amount of inflammatory mediators releasedby objects like monocyte-macrophage cells and form pro-gressively larger “waterfall-like” chain reaction. TNF-alfa, IL-6, and its mediated cascade play a key role in the pathogenesisof SIRS and MODS [18, 19].

Results for meta-analysis showed that CVVH was ableto eliminate inflammatory mediators (TNF-alfa, IL-6) inplasma effectively, lower WBC count, shorten hospital stays,and better stabilize hemodynamics to a greater extent thanconventional therapeutic measures. Meanwhile there is nosignificant difference in mortality between the two groups.

As we know, TNF-alfa and IL-6 affect a wide varietyof cells to induce many similar inflammatory reactions:fever, production of cytokines, endothelial gene regula-tion, chemotaxis, leukocyte adherence, and activation offibroblasts. They are responsible for the systemic effects ofinflammation, such as loss of appetite and increased heartrate. Meta-analysis also reports inflammatory mediators(TNF-alfa, IL-6) and WBC count is significantly reducedin CVVH group. Removal of inflammatory mediators,decrease of inflammatory mediators’ body concentration,and keeping the balance of body proinflammatory systemand anti-inflammatory system have become ideal therapeuticstrategies for those diseases. CVVH treatment in the earlystage of MODS patients can decrease or break partly stop therelease of cytokines and can improve prognosis [6]. However,Payen et al. study suggests that early application of standardcontinuous venovenous hemofiltration is deleterious insevere sepsis and septic shock [16].

Nine trials reported the mortality rate, the results ofmeta-analysis show that there are no significant differencesbetween the two groups [6–14, 16]. Some of the trialswas discontinued after There are some reasons like clinicalheterogeneity, trial was discontinued after many patientsdied, limited sample size and limited effect of CVVH canexplain it. However, this is a very critical outcome and shouldbe studied carefully in following trials.

Length of hospital stay results from the studies includedin this meta-analysis showed that CVVH significantlyreduced length of hospital stay as compared with the controlgroup by 5.3 days. The results are due to the benefits ofremoval of inflammatory mediators. Reducing length of stayby this amount for every patient is likely to make a significantdifference to cost of patient care.

Two studies reported hemodynamic stability [6, 7].During 48-hour followup, CVVH could keep hemodynamicstability. However, to those SIRS/MODS patients, long-termhemodynamic observation is needed.

All of the included studies offered adequate descriptionsof the randomization process. Only two studies offered allo-cation concealment [7, 9]. Although blinding of patients andcaregivers may not be feasible in CRRT studies, allocationconcealment and blinding of data collectors and outcomeassessors are possible and desirable. However, blinding,in all of the trials, was not stated, which would yieldselection bias and performance bias. Furthermore, only twostudies reported intention-to-treat analysis, which wouldyield attrition bias [9, 16]. All studies reported incompleteoutcome data. Due to these methodological limitations, aswell as the statistical imprecision and heterogeneity, thequality of evidence presented in this article is considered oflesser quality.

Our meta-analysis also had its limitations. First, therewas inability to assess and estimate effects of baseline patientcharacteristics because access to individual patient data waslimited. Second, different types of filter membranes usedmay have had a different impact. The characteristics of themembrane used in CVVH may be an important factor oncytokine clearance. The use of different membranes maylead to variable TNF and IL-6 extraction. Third, all of theincluded studies focused on only two inflammatory medi-ators, (TNF-alfa, IL-6). Perhaps other mediators like IL-1,

ISRN Hematology 5

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ISRN Hematology 9

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10 ISRN Hematology

IL-8, platelet activating factor (PAF), and so forth, can betested. Fourth, some data should be assessed using weightedmean differences, or only the descriptive analysis can be used.Finally, some of the inclusion studies were from China, sothe results should be considered carefully when they wereapplied to other countries. Therefore, we still need morehigh-quality, multicenter, randomized, and controlled trialsfrom other countries and regions.

5. Conclusions

All in all, CVVH could eliminate inflammatory mediators(TNF-alfa, IL-6) in plasma effectively, shorten hospital stays,and better stabilize of hemodynamics. This is worthy offurther exploration and promotion. As an exogenous way ofclearance, CVVH has aroused great concern because its effecton clearing inflammatory mediators and its mechanism ofclinical effects in the treatment of critical illness will alsobecome of more and more perspective in research and appli-cation.

Conflict of Interests

There is no financial support or relationships that may poseconflict of interests in this paper.

Acknowledgments

The first author the coauthors and all authors, who have con-tributed significantly. All authors are in agreement with thecontent of the paper.

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